An antiallergic drug, tranilast, has been commercially available as a therapeutic agent for allergic diseases. It has also been reported to show excellent pharmaceutical effect on keloid and hypertrophic scar (Kiyoshi Ichikawa et al., Oyo Yakuri (Pharmacometrics) 43(5), 401 (1992), Haruo Suzawa et al., Nichi Yakuri-shi (Folio Pharmacol Japan) 99, 231 (1992)). Tranilast has been used in the dosage form for oral administration such as capsules, tablets, dry syrup, fine granules, and the like. However, the drug orally taken is absorbed from the digestive tract through portal vein to liver where the drug is metabolized to give a so-called first passing effect. Thereafter, a part of the drug is transferred to local sites and its biological availability is decreased. Accordingly, it is necessary to administer a relatively large amount of the drug so as to maintain the effective drug concentration in blood, which increases manifestation of side effects. Further, preparations for external application directly applied to local sites of skin, particularly patches, have been considered favorable for the treatment of keloids, hypertrophic scar, and allergic dermatitis so that it is necessary to maintain an effective drug dosage sufficiently in the skin.
Attention has been paid to patches as preparations for topical application as well as a new route for applying systemic drugs as transdermal drug delivery system (TDS). In other words, in TDS, a drug absorbed from its preparation through epidermis is taken into blood stream via subcutaneous capillary vessels while a portion of the drug is transferred directly to local skin tissues without being taken into blood stream. Aiming at such a topical application effect, a number of patches utilizing non-steroid anti-inflammatory drug systems (NSAIDS) have been already developed and commercially available.
Further, subcutaneous application by patches is effective as the controlled release method of drugs by which effects of drugs can be prolonged and the concentration of drugs in blood can be controlled. Thus, it is possible to suppress manifestation of side effects.
However, skin inherently has a property to defend the inside of body from foreign substances that may invade from the outside. Keratolytic agents such as Azone are sometimes used as a base in order to increase transdermal absorption of a drug. Such agents give high skin irritation and thus may possibly cause side effects such as an eruption on the skin. Transdermal absorbability depends on characteristics of the molecule, which extremely limits formulation of the drugs that can give effective transdermal absorption.
Tranilast is sparingly soluble in water. Among organic solvents, it is hardly soluble in methanol, ethanol, ethyl acetate, while it is soluble in dimethyl formamide, pyridine, dioxane, and acetone though these solvents are not suitable for the base of preparations for external application. The drug can be solved to some extent in a kind of fatty acid and its ester, animal and vegetable oils and fats, terpene compounds, and alcohols, but the solubility is not sufficient and the drug cannot be dispersed well in the preparations. This affects transdermal absorbability of tranilast and the solubility of the drug makes it difficult to formulate the drug into a patch.
As a preparation containing tranilast for external application, a patch containing tranilast has been developed, which contains a kind of fatty acid and alcohols as absorption aids to improve cutaneous absorbability (Japanese Patent Application Laid-Open No. Hei 4-99719). However, this patch requires a large amount of absorption aids, such as fatty acid ester or alcohols, which might possibly cause skin irritation.
A tranilast-containing ointment has also been developed, which contains a basic aqueous solution as an absorption aid (Japanese Patent Application Laid-Open No. Hei 6-128153). This preparation for external application has basic pH due to the basic aqueous solution contained as an absorption aid. The basic substance itself might possibly cause skin irritation. Thus, there are problems that make it difficult to put the preparations into practical use.